In recent years, various vaccines have been developed using physiologically active substances. Some of these physiologically active substances, however, cannot be (sufficiently) filter-sterilized, for example, due to their low water solubility. Also, some physiologically active substances are difficult to dissolve in an aqueous solution or an emulsion prepared from the aqueous solution for administration to organisms such as humans.
Various methods have been attempted to improve the water solubility of drugs such as physiologically active substances. For example, a carrier-drug conjugate (so-called drug derivative) is known in which a highly water-soluble carrier is artificially added directly to a drug. A hydrophilic amino acid sequence or polyethylene glycol (PEG), etc., is known as the carrier.
Such a drug derivative, however, in which a carrier is bonded directly to a drug, differs in steric structure from the original drug. The resulting drug derivative exhibits different pharmacokinetic, immunogenic, toxicological, or pharmacological properties compared with the original drug molecule. Particularly, when the drug derivative is used as, for example, a vaccine, the antigenicity of this drug derivative is well known to be usually lower than that of the original drug molecule.
A drug with PEG added as a carrier (PEGylated drug) is resistant to biodegradation. Thus, the PEGylated drug, when continuously administered into an organism, has the risk of accumulating in the organism to cause chemical injury to the organism; thus its biocompatibility is still less than sufficient (Patent Literature 1). Furthermore, PEG has a molecular weight distribution (polydisperse nature). The PEGylation of drugs forms many monomeric isoforms (many different monomeric isoforms: structurally different proteins having the same functions), because of the difference in the binding site or molecular weight of added PEG. These formed isoforms might compete with each other for binding to a drug acceptor molecule (Non Patent Literature 1).
A carrier-linker-drug conjugate has also been developed in which a drug and a carrier are bonded via a linker moiety. This conjugate can be designed such that the bond between the carrier-linker moiety and the drug is cleaved upon acting on a target site (in blood, etc.) to release the drug itself. In the case of using such a carrier-linker-drug conjugate, light or enzymatic cleavage has been used as a trigger for the cleavage of the bond between the carrier-linker moiety and the drug. Unfortunately, for the use of the light, the light irradiation to the target site is difficult, and damage to the organism is also a concern. Alternatively, in the case of the enzymatic cleavage, the amount of an enzyme is known to largely differ not only among individuals but depending on administration sites. Thus, the problem of this approach is to cause variations in the effect of the drug therapy among patients.
In response to these problems, a carrier-linker-drug conjugate has been reported in which a carrier-linker moiety is bonded via an amide group to a physiologically active substance moiety (Patent Literature 2). The technique disclosed in Patent Literature 2 utilizes autohydrolysis based on an intramolecular catalytic effect in the carrier-linker moiety so as to control the cleavage of the bond between the carrier-linker moiety and the drug. The mechanism underlying the cleavage of the bond between the carrier-linker moiety and the physiologically active substance moiety is based on the cyclization-activation resulting from cyclic imide formation for cleavage of the amide bond.